c-FLIP is a key anti-apoptotic factor that is over-expressed in many tumors and blocks the apoptotic machinery by interfering with FADD, caspase-8 and DR5. Significant evidence demonstrates that c-FLIP over-expression in tumors is a major cause of resistance to TRAIL-induced apoptosis. Therefore, strategies to inhibit c-FLIP action and to overcome c-FLIP-induced resistance in tumor cells may lead to novel and more effective therapies. We have discovered a bioactive peptide, ApoFLIP that antagonizes with c-FLIP and reinstates the apoptotic machinery in c-FLIP expressing cells. The major goal of this proposal is to develop and characterize drug-like variants of this peptide. These agents could provide significant enhancements in the current therapeutic strategies in hematological malignancies and other tumors that show resistance to apoptosis-inducing therapeutics.